The subject matter disclosed herein relates to a method of enhancing the effectiveness of Interleukin-24 (IL-24) cancer therapy.
An adenovirus expressing Interleukin-24, Ad.IL-24 (INGN 241), is known to exhibit activity by intratumoral injection in patients with advanced solid tumors. The use of Ad.IL-24 is safe and able to induce as much as 70% apoptosis in tumors after a single injection of recombinant virus and multiple injections generate clinical responses. Moreover, secreted IL-24 protein, generated from Ad.IL-24-infected cells, promotes antiangiogenic, immunostimulatory, radiosensitizing and “bystander” antitumor activities. IL-24 as a cancer gene therapeutic has several advantages over other candidate molecules, including high tumor cell specificity, anti-angiogenic properties, ability to radiosensitize, as well as cause growth-suppressive effects that are independent of p53, p16, Rb and BAX mutational status. In addition, IL-24 may be used in conjunction with existing p53-based therapeutics and has shown potential synergism with immuno- and chemo-therapy, potentially allowing a reduction in dose of all components in a given therapy. However, despite the extensive studies, questions remain about how IL-24 exerts its tumor-specific effect.
IL-24 is a member of the IL-10 family of cytokines. IL-24 binds to IL-20 receptor liccomplexes and activates TAT T signaling cascade. IL-24 possesses the properties of a classical cytokine as well as a tumor suppressor protein. When expressed at supraphysiological levels, by means of an adenoviral (Ad) expression system (Ad.IL-24), IL-24 induces growth suppression and apoptosis in a broad spectrum of human cancer cells, without exerting any deleterious effects on their normal counterparts. Furthermore, secreted IL-24 protein generated from Ad.IL-24 infection, induce cancer-specific apoptosis. Ad.IL-24 induces cancer-selective apoptosis even in the absence of JAK/STAT signaling. As evidenced by the expression of ER stress markers (BiP, CHOP, and phospho-eIF2a) Ad.IL-24 or secreted IL-24 protein, induce ER stress. Ad.IL-24 or secreted IL-24 protein also generates reactive oxygen species (ROS) in the mitochondria. Ad.IL-24 induces ceramide production in cancer cells. Adenovirus delivery of IL-24 inhibits f3-catenin and phosphatidylinositol 3′-kinase signaling pathways in lung cancer cells and activates Fas-FasL signaling in ovarian cancer cells. Infection of melanoma cells with Ad.IL-24 results in activation of death ligands (FasL), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and their respective death receptor signaling pathways.
Secreted IL-24 protein has been shown to induce a robust expression of endogenous IL-24 and subsequent induction of tumor-specific killing through an ER stress-mediated pathway as well as by ROS production. IL-24 protein has been shown to induce stabilization of its own mRNA without activating its promoter. Ad.IL-24 has been shown to induce p38MAPK. The p38MAPK has been shown to regulate IL-24 expression by stabilization of the 3′UTR of their mRNA. The ER stress pathway is believed to be the initial pathway in IL-24-induced apoptosis. IL-24 may cause ER stress by physically interacting with the ER chaperon protein BiP. IL-24:BiP binding might be mediated by the interaction of IL-24 with as yet unidentified protein that confers cancer cell specificity. The precise molecules mediating this pathway remain unclear. An improved method of IL-24 cancer therapy is therefore desired.
The discussion above is merely provided for general background information and is not intended to be used as an aid in determining the scope of the claimed subject matter.